A bromodomain (BRD), present in some proteins, is a conserved structural motif that binds to N-acetylated lysine residues of various proteins. BRDs occur as functionally distinct modules in a variety of proteins including chromatin-associated proteins, histone acetyltransferases and transcriptional activators. Inhibitors of the interaction between a bromodomain and its cognate N-acetylated protein binding partner are believed to be useful in the treatment of a variety of diseases or conditions, such as cancer as well as chronic autoimmune and inflammatory conditions.
The Bromodomain and Extra-C Terminal domain (BET) protein family is comprised of four members (BRD2, BRD3, BRD4 and BRDT). BRD2, BRD3 and BRD4 are expressed ubiquitously whereas BRDT expression is largely limited to the testis. Each member of the BET family possesses two bromodomain motifs that bind N-acetylated lysine residues on the amino-terminal tails of histone proteins. Once bound these proteins modulate gene expression by affecting chromatin status and recruiting transcription factors to specific genome locations within chromatin. For example, BRD4 and BRDT independently recruit CDK9 and cyclin T1, which together constitute the catalytic subunit of the positive transcription elongation factor b (P-TEFb). This results in phosphorylation of the carboxy-terminal domain (CTD) heptad repeat of RNA Polymerase II, thereby facilitating transcription elongation and the expression of a subset of genes involved in cell cycle progression. BRD2 and BRD3 have been shown to associate with several transcription co-activators and/or co-repressors, which regulate transcription control of various genes including cyclin A and cyclin D1. In addition BRD2 and BRD4 have been reported to possess atypical kinase activity and BRD4 has also been reported to bind to acetylated RelA, a sub-unit of NF-κB.
BET family members have recently been shown to be involved in the maintenance and progression of several cancer types including leukaemia, lymphoma, multiple myeloma and solid tumours such as non-small cell lung cancer, osteosarcoma and glioblastoma. The fusion between BRD4 (and to a lesser extent BRD3) with the nuclear protein in testis (NUT) gene leads to squamous cell carcinomas known as NUT midline carcinomas (NMC). BET family members have also been implicated in mediating acute inflammatory responses and in HIV-associated kidney disease. BRD2 function has also been linked to obesity and Type II diabetes. The human immunodeficiency virus utilizes BRD4 to initiate transcription of viral RNA from stably integrated viral DNA. BET bromodomain inhibitors have also been shown to reactivate HIV transcription in models of latent T cell infection and latent monocyte infection. BRDT has an important role in spermatogenesis and disruption of normal BRDT binding to acetylated histones may have utility as a male contraceptive.
Therefore, there is an ongoing medical need to develop new drugs to treat diseases and indications involving bromodomain function, including BET bromodomain function.
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